The United States of America, As Represented by the Secretary, Department of Health and Human Services

Novartis Ag

University of Washington

The United States of America As Represented by the Department of Health

The United States of America As Represented by the Secretary of

Admune Therapeutics LLC

George N Pavlakis

Barbara K Felber

Cristina Bergamaschi

Antonio Valentin

John N Vournakis

Sergio Finkielsztein

Nancy Smyth-Templeton

James I Mullins

Genoveffa Franchini

George A Gaitanaris

Zdenek Hel

John V Vournakis

James Tartaglia

Alexander Gragerov

Roland H Stauber

Sergey V Smulevitch

Margherita Rosati

Filomena Nappi

Siriphan Manocheewa

Sergio Finkielszttein

The present invention provides for nucleic acids improved for the expression of interleukin-15 (IL-15) in mammalian cells. The invention further provides for methods of expressing IL-15 in mammalian cells by transfecting the cell with a nucleic acid sequence encoding an improved IL-15 sequence. The present invention further provides expression vectors, and IL-15 and IL 15 receptor alpha combinations (nucleic acid and protein) that increase IL-15 stability and potency in vitro and in vivo. The present methods are useful for the increased bioavailability and biological effects of IL-15 after DNA, RNA or protein administration in a subject (e.g. a mammal, a human).

Codon optimized IL-15 and IL-15R-alpha genes for expression in mammalian cells

The invention provides methods and compositions for eliciting broad immune responses. The methods employ nucleic acid vaccines that encodes highly conserved elements from a virus.

Altering the immundominance hierarchy using a DNA vaccine expressing conserved regions

The present invention relates to agents that modulate interleukin-15 ('IL-15') signal transduction or function ('Therapeutic Agents') and the use ol&#x201d; those agents to modulate immune function. The Therapeutic Agents target the interaction between IL-15 and its receptor and modulate IL-15-induced signal transduction. The Therapeutic Agents may be formulated with polymers, such as poly-&#x3b2;-1-&#x2666;4-N-acetylglucosamine. for administration to a human subject to modulate IL-15-mediated immune function.

Complexes of IL-15 and IL-15Ralpha and uses thereof

The present invention provides method for promoting the maturation and export of T cells from thymic tissue by contacting the thymic tissue with supraphysiological levels of interleukin (IL)-15. The present invention also provides methods for preventing, alleviating, reducing, and/or inhibiting lymphopenia or peripheral depletion of lymphocytes in a patient in need thereof by administering to the patient IL-15.

Heterodimers of IL-15 and IL-15R alpha to increase thymic output and to treat lymphopenia

Use of IL-15 to increase thymic output and to treat lymphopenia

The present invention provides for nucleic acids improved for the expression of interleukin-15 (IL-15) in mammalian cells. The invention further provides for methods of expressing IL-15 in mammalian cells by transfecting the cell with a nucleic acid sequence encoding an improved IL-15 sequence. The present invention further provides expression vectors, and IL-15 and IL-15 receptor alpha combinations (nucleic acid and protein) that increase IL-15 stability and potency in vitro and in vivo. The present methods are useful for the increased bioavailability and biological effects of IL-15 after DNA, RNA or protein administration in a subject (e.g. a mammal, a human).

Described herein are dose escalation regimens for the administration of complexes comprising interleukin-15 ('IL-15') covalently or noncovalently bound to IL-15 receptor alpha ('IL-15R&#x3b1;') to patients in order to enhance IL-15-mediated immune function. In a specific aspect, the dose escalation regimens are useful in the prevention, treatment, and/or management of disorders in which enhancing IL-15-mediated function is beneficial, such as cancer, infectious diseases, immunodeficiencies and lymphopenia. In another specific aspect, the dose escalation regimens are useful for eradicating or reducing HIV in HIV-infected patients.

IL-15 and IL-15R&#x3b1; heterodimer dose escalation regimens for treating conditions

The present invention relates to agents that modulate interle&#x3c5;kin-15 ('IL-15') signal transduction or function ('Therapeutic Agents') and the use ol&#x201d; those agents to modulate immune function. The Therapeutic Agents target the interaction between IL-15 and its receptor and modulate IL-15-induced signal transduction. The Therapeutic Agents may be formulated with polymers, such as poly-&#x3b2;-1-&#x2666;4-N-acetylglucosamine. for administration to a human subject to modulate IL-15-mediated immune function.

The present invention relates to agents that modulate interleukin-15 ('IL-15') signal transduction or function ('Therapeutic Agents') and the use ol&#x2033; those agents to modulate immune function. The Therapeutic Agents target the interaction between IL-15 and its receptor and modulate IL-15-induced signal transduction. The Therapeutic Agents may be formulated with polymers, such as poly-&#x3b2;-1-&#x2666;4-N-acetylglucosamine. for administration to a human subject to modulate IL-15-mediated immune function.

Cell expressing complexes of IL-15 and IL-15Ralpha

The present invention provides methods of improving the levels and stability of expression of interleukin-12 family cytokine polypeptides by expressing the alpha and beta subunits of the polypeptides at their determined relative molar ratios that increase the levels and stability of expression of the heterodimer, e.g., in comparison to heterodimer expressed at an equimolar ratio.

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Rockville, MD, United States of America

George N Pavlakis